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Original Studies |
Department of Biological Sciences, University of Warwick (K.L., C.J.O., G.F.M., P.O.), Coventry, United Kingdom CV4 7AL; the Department of Endocrinology, Medizinische Hochschule (R.H., G.B.), D-30623 Hannover, Germany; and Royal United Hospital (D.D.), Bath, United Kingdom
Address all correspondence and requests for reprints to: P. O’Hare, M.D., F.R.C.P., Department of Biological Sciences, University of Warwick, Coventry, United Kingdom CV4 7AL.
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Abstract |
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Diabetic subjects, however, had significantly higher soluble leptin receptor levels at all stages (P < <0.001), which rose further in the third trimester from 3742 ± 268 (mean ± SEM) to 4134 ± 239 pmol/L, whereas in the normal group there was a fall from 3149 ± 169 to 2712 ± 123 (P = 0.05). There is a linear relationship between the soluble leptin receptor levels and the body mass index in the diabetic group only.
We conclude that there is no significant difference in free or bound leptin levels between the normal and insulin-dependent diabetic subjects either during pregnancy or postpartum, but female insulin-dependent diabetic subjects have significantly higher soluble leptin receptor levels. We speculate that high soluble leptin receptor levels might be implicated in the development of the leptin resistance in this group.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several alternatively spliced isoforms of leptin receptor have been identified (Ob-Ra, Ob-Rb, and Ob-Re). Ob-Re is a soluble form of a transmembrane leptin receptor (9). Soluble leptin receptor (Ob-Re) has been shown to be capable of binding leptin at a 1:1 ratio (10). Sinha et al. (7) postulated that the soluble form of the leptin receptor may form about a 10% fraction of the leptin-binding proteins.
Although a human equivalent of the ob/ob mice mutation has been recently discovered (11, 12), and now there is also evidence of the presence of leptin receptor defects in humans (13), there is no evidence to date of the presence of an equivalent of the db/db mice or fa/fa rat mutations in the majority of obese human individuals (14). As the latter genotypes are known to involve a mutation of the extracellular domain of the Ob-Rb leptin receptor that results in severe leptin resistance, the roles of leptin and its receptor defects in human subjects remain unclear.
Pregnancy constitutes a unique model for the investigation of adipose tissue metabolism, as it is associated with profound alterations in hormonal metabolism. These changes include hyperinsulinemia and insulin resistance together with large increases in the concentrations of cortisol, estrogens, progesterone, and human placental lactogen. The first two trimesters of pregnancy are considered to be predominantly anabolic, and pregnant women normally deposit a certain amount of fat stores (15). The last trimester of pregnancy is characterized by increased catabolism, increased lipolysis, elevations of the concentrations of free fatty acids, minimal or no fat deposition, and significant increases in triglyceride concentrations, probably as a part of the physiological preparation for lactation (16, 17, 18, 19).
Leptin, as a hormone produced by adipose tissue and also secreted by the placenta, could play a role in complicated interactions involving the regulation of appetite and fat metabolism in human pregnancy. Leptin levels have been reported to be elevated during pregnancy in rats (20) and humans (21, 22, 23, 24), probably as a result of placental leptin secretion (25, 26). Leptin levels also correlated with fetal birth weight, although there was no obvious correlation between maternal leptin levels and fetal growth (27).
The assessment of the components of the leptin system (free leptin, bound leptin, and a soluble leptin receptor) during pregnancy may be particularly interesting, as we know that chronic hyperinsulinemia has been reported to be associated with elevated leptin levels (28, 29). Insulin is known to increase the synthesis of leptin messenger ribonucleic acid in human adipocytes, and its effect is even further potentiated by cortisol (30). Type II diabetic subjects treated with insulin have higher leptin levels than their weight-matched controls receiving oral treatment (31, 32). Male insulin-dependent diabetes mellitus (IDDM) subjects were also reported to have higher leptin levels (33), and it is known that intensive insulin regimens (such as employed in the management of IDDM pregnancy) are associated with increased weight gains (34, 35). This may suggest the presence of some form of leptin resistance in this group.
To date, it is not known how different leptin subfractions (free leptin, bound leptin) change during normal or diabetic pregnancy. We know that pregnancy is normally associated with significant fluctuations of several hormone-binding proteins (36, 37). Although the soluble leptin receptor is known to be one of the leptin-binding proteins, its role in leptin physiology has not been fully explored.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.
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Characterization of assays
Polyclonal antibodies to a C-terminal [leptin-(126–140)] and an N-terminal fragment of leptin [leptin-(26–39) (25Tyr); Saxon Biochemical, Hannover, Germany], both coupled to hemocyanin by the carbodiimide method, were generated in rabbits. Both fragments were chosen on the basis of a lack of any known homology to other proteins according to the Swiss-Prot databank. The C-terminal peptide naturally contained a Tyr residue, allowing easy radiolabeling of the fragment for detection. Amino acid 25 of the N-terminal peptide was changed from Gln to Tyr to allow for iodination. Antibodies were used in a final dilution of 1:1500 in the C-terminal assay and 1:2000 in the N-terminal assay; 5,000 and 20,000 cpm labeled fragment, respectively, served as tracer. The C-terminal assay has been described previously by Horn et al. (38). The intra- and interassay variations of this assay are 4.8% and 8.3%, respectively.
Rabbits were immunized with a fragment (amino acids 354–368; Saxon Biochemical) of the extracellular domain of the human leptin receptor to detect circulating forms of the short soluble receptor. Again, no sequence homology to any other protein in the Swiss-Prot databank was detected, and again a naturally occurring Tyr in the sequence allows for easy radiolabeling. The antibody was used in an end dilution of 1:1,000 in an assay using 15,000 cpm labeled fragment for a tracer. Separation of bound and free peptide was achieved by 2% dextran-coated charcoal in all assays.
To characterize the assay specificity, we tested the N- and C-terminal
antibodies directly with recombinant human full-length bioactive leptin
(gift from L. A. Campfield, Hoffmann-La Roche, Nutley, NJ) and
recombinant extracellular human receptor protein (gift from P. Devos,
Hoffmann-La Roche, Ghent, Belgium). Parallelity of dilution curves of
sera with the standard curves was shown in all three assays (data not
shown). Leptin receptor antibodies were characterized by Western
blotting showing a single band that corresponds to the expected
molecular size of 90 kDa (data not shown). Figure 1 shows the results of Sephadex G-200
chromatography. Investigation of pooled sera revealed a single peak
with a molecular size of 15–20 kDa, equivalent to the expected size of
free leptin when the C-terminal antibodies were used for detection. As
reported previously, leptin immunoreactivity detected with this assay
corresponded well to recombinant human leptin. In contrast, the same
fractions from gel chromatography measured with the N-terminal assay
showed no immunoreactivity in the samples corresponding to a molecular
mass of unbound leptin. However, two peaks with molecular sizes of
approximately 200 and 100 kDa were detected. The identical fractions
showed positive immunoreactivity with the leptin receptor
antibodies.
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Statistical analysis
The design of this observational study, in which multiple measurements were made within a patient, created a hierarchical data structure. Although the patient was the actual sampling unit, the unit of interest and hence the unit of analysis were, in fact, the leptin or soluble receptor. Although, by definition, the patients were matched by gender and approximately for age, measurements within the same patient were expected to be more alike than those between patients. The use of statistical methods that make the assumption that observations are independent (i.e. ignoring the correlation within a patient), could result in spurious statistical inference. Hence, analysis of the data was performed by means of generalized linear mixed (fixed and random effect) hierarchical (patient and observation level) statistical models, by which total observed variation could be apportioned to that occurring between patients vs. within a patient. Models were generated using MLn software (Institute of Education, London, UK), and the significance of model parameters was assessed by maximum likelihood methods. Model fit and underlying distributional assumptions were assessed by examination of standardized residuals.
As we possessed no data on the exact amount of body fat for each individual and the stage of gestation, the leptin and soluble receptor levels determined could not be directly related to the precise amount of body adiposity (e.g. per kg fat mass). For each outcome variable, within the constraints of the method, we have constructed a model that included stage of gestation and diabetic status as the only covariates to the model building process [thus ignoring the changes in body mass index (BMI)] as well a more inclusive model in which other explanatory variables (e.g. BMI) were also tested. Where appropriate, comparisons of patient characteristics between groups were accomplished using an unequal variance and paired t test. Unless specified otherwise, the data for free leptin, bound leptin, and soluble leptin receptor are presented as the mean ± SEM in picomoles per L.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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as the
mean, SD, and range. There was no significant difference in
age between normals and diabetics (P = 0.91), nor was
there a difference in gestational weight gain from 20–30 weeks between
the two groups (P = 0.29), although diabetic subjects
had significantly greater variability in weight gain (by F test,
P = 0.036). Fetal birth weight was lower in the
diabetic group (P = 0.03) and more variable (by F test,
P = 0.02; Table 1). As expected, the BMI increased significantly from 20–30 weeks of gestation by an average of 1.83 kg/m2 per individual (P < 0.001), with a significant postpartum fall to values lower than that at 20 weeks gestation (average fall, 1.48 in comparison to the 20 week value (P < <0.001). There was no significant difference in the BMI between normals and diabetics at any stage (P = 0.61), and therefore we assume that the investigated groups were effectively matched for both age and BMI.
Mean free and bound leptin levels (mean ± SEM;
picomoles per L) are presented in Table 2. Figure 2, A and B, present the summary
information for free and bound leptin levels and soluble leptin
receptor in normal and diabetic subjects by stage of gestation. Free
and bound leptin levels were normally distributed in both groups, with
variability between individuals much greater than the variability
within the same individual at different stages of gestation, with
values of 70% and 77% of the total observed variation, respectively.
Inclusion of BMI in the models resulted in a decrease in the
within-individual variation by approximately 27%, 1%, and 4% for
free leptin, bound leptin, and soluble leptin receptor, respectively.
There was no significant difference in the free leptin levels between
the normal and diabetic subjects at any stage (P =
0.34) when the BMI variable was included in the statistical analysis.
There was also no significant difference in the bound leptin levels
between the investigated groups (P = 0.84). This
allowed us to combine the data on the free and bound leptin levels in
normal and diabetic subjects and to analyze them as a single group
(n = 39).
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). A smaller (
60%), but
significant, rise was observed during pregnancy for the bound leptin
subfraction, the levels of which were also significantly lower
postpartum (P < 0.001; Table 2). The rise in leptin
levels observed during pregnancy was out of proportion to the expected
pregnancy-related increase in body adiposity.
The increase in total leptin levels between 20 and 30 weeks gestation
(P = 0.009; Table 2) was attributable to the rise in
the bound leptin subfraction (P = 0.034; Table 2), as
there was no significant change in free leptin levels between the
second and third trimesters (P = 0.17; Table 2). Bound
leptin levels postpartum were significantly lower those than at 30
weeks (P < <0.001), but only marginally lower than
those at 20 weeks, (P = 0.049). Despite overall changes
in leptin levels, relatively high or low free or bound leptin
concentrations tended to persist within the same individual throughout
the study, i.e. women with high free and/or bound leptin
levels at 20 weeks gestation were also likely to have higher free
and/or bound leptin levels at 30 weeks gestation or postpartum.
It is of interest to note that no rise in the free leptin levels was observed between 20–30 weeks gestation in the diabetic group despite a significant rise in insulin requirements (mean ± SEM, 58 ± 5.3 U/24 h vs. 87 ± 12.6; P = 0.004, by paired t test). Insulin requirements subsequently fell postpartum to 49 ± 4.0 U/24 h (P = 0.02, by paired t test).
Inclusion of the BMI in the modeling process allowed us to demonstrate
the presence of a linear relationship between the BMI and the free and
bound leptin levels for normal and diabetic subjects for different
stages of gestation and postpartum (Fig. 3, A and
B, respectively). The level of free leptin was positively linearly
related to the BMI of a given patient; however, this relationship was
significantly greater (P < <0.001) for a given
individual at 20 weeks gestation than at 30 weeks gestation or
postpartum, which did not differ significantly (P =
0.16). Once the relationship between the changing BMI and free leptin
levels had been accounted for, there was no significant decline in free
leptin levels postpartum that could not be related to the simultaneous
decline in BMI.
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) were also linearly associated with
the BMI of any given patient (P = 0.022), but the slope
was consistent at all stages. Further, having controlled for this
linear relationship with BMI, there remains a uniform elevation in the
bound leptin level, i.e. regardless of patient BMI, at 30
weeks gestation (P = 0.018).
Although statistical modelling for free and bound leptin consistently
showed no significant difference between normal and diabetic groups, in
the case of the soluble leptin receptor, the models demonstrated
significantly higher soluble leptin receptor levels for diabetics than
for normal subjects (P < <0.001; Fig. 2B). Further,
once the difference between normals and diabetics had been accounted
for, the patient level variance estimate was not significantly
different from zero for the model with (P = 0.89) or
without (P = 0.67) BMI, and hence both models were
reduced to single level simple regression. That is, within the normal
and diabetic groups, the vast majority of the variation in soluble
receptor levels was between observations, rather than between patients.
An inclusion of the BMI into the analysis additionally allowed us to
demonstrate that the soluble leptin receptor levels were not only
significantly higher for the diabetic subjects across the range of
observed BMI values, but they were also linearly related to the BMI
(P < 0.001) regardless of the stage of gestation. That
is, in the diabetic group, those with higher BMI also had higher
soluble receptor levels, whereas this was not true for the normal
subjects (P = 0.31). We also observed the presence of a
positive relationship between the 24-h insulin requirements and the
soluble leptin receptor levels, although this relationship could be
explained by the presence of a simultaneous relationship between the
BMI and the 24-h insulin requirements. Furthermore, controlling for
this relationship between the BMI and the soluble leptin receptor
levels, we observed a borderline significant (P =
0.05), but interesting, difference in the pattern of change in the
soluble leptin receptor levels between the 20–30 weeks gestation, with
a rise in a diabetic group from 3742 ± 268 to 4134 ± 239
pmol/L and a fall in the normal group from 3149 ± 169 to
2712 ± 123 pmol/L (Table 2). In neither group was the subsequent
postpartum change statistically significant (P = 0.58).
Figure 3C schematically represents the mean relationship between the
soluble leptin receptor levels and the BMI for normal and diabetic
subjects by stage of gestation.
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Discussion |
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The BMI in pregnancy is an indirect and very imprecise measure of the amount of body fat stores, as it includes the weight of the fetus, placenta, amniotic fluid, and maternal fluid expansion, and therefore may not be simply compared to the postpartum values. The relationship of leptin to gestational weight and fat gain is unfortunately further complicated, because the exact estimation of gestational fat gain remains difficult, mostly as a result of inaccuracies in the calculation of maternal extracellular fluid gain (39, 40, 41, 42). Unlike Peterson et al. (43), who showed greater weight gain in pregnant diabetic women in early pregnancy, we did not detect any significant difference in gestational weight gain between normal and diabetic subjects. This might be explained because these diabetic subjects were highly motivated and very well metabolically controlled. One must also bear in mind that the relationship between the weight gain and the actual fat gain in pregnancy is complicated, and due to the methodological inaccuracies, the calculated fat gain between different stages of pregnancy may vary as much as 50% depending on the method used (40, 41). We should note, however, that free leptin levels in pregnancy are about 100% higher than those postpartum, and this rise is much higher than the average gestational fat gain, which according to King et al. (15) is usually between 25–30%.
No change in the free (i.e. presumably biologically active) leptin subfraction is observed between 20–30 weeks gestation despite the fact that significant fat deposition is known to take place during that time (36). The average amount of fat gain during this period, however, may be too small to detect any significant change in free leptin levels, particularly in view of the known placental leptin secretion in human pregnancy (25). We also did not observe any rise in the free leptin subfraction despite the rise in insulin requirements between the second and third trimesters. Chronic hyperinsulinemia is associated with elevated leptin levels, although it is not entirely clear to what extent this relationship may be modified by pregnancy and by placental leptin secretion. Insulin is known to be involved in fat storage (44) through stimulation of preadipocyte replication, preadipocyte differentiation, and possibly also suppression of adipocyte apoptosis (45). As these processes are all active in pregnancy, we can only speculate that high amounts of leptin secreted by the placenta could obscure any changes in leptin concentrations related to pregnancy-induced hyperinsulinemia.
Gavrilova et al. (46) reported a particularly striking
(40-fold) increase in the concentrations of leptin-binding proteins
(formed predominantly by the soluble leptin receptor) during pregnancy
in ob/ob mice. The observed rise in leptin-binding proteins
resulted in an equally striking (40-fold) rise in total leptin levels.
This phenomenon was caused predominantly by an increased placental
shedding of membrane receptor to form the soluble leptin receptor. In
our study of human pregnancy we failed to detect such a high
pregnancy-related increase in the soluble leptin receptor levels. The
proportional rise in free leptin levels (100%) was also higher than
the rise in the bound fraction (60%). The observed rise in the
total (i.e. free and bound) leptin levels more closely
resembled the changes observed during pregnancy in rats (20), in which
an approximately 1.8-fold increase in leptin levels has been reported.
Our study therefore constitutes yet another example of significant
differences in physiological regulation of the leptin system that exist
between the human and the ob/ob mouse model.
IDDM subjects in our study were found to have significantly elevated soluble leptin receptor levels, which increased further in the third trimester despite the absence of any differences in free or bound leptin levels. We know that leptin receptor belongs to the class I cytokine receptor family (9, 10), an example of which is the hGH receptor (47). Soluble GH receptor, known as a GH-binding protein, has been described as a model of a situation, where a circulating extracellular domain of the membrane receptor is known to modulate the function of the membrane receptor by competing in the process of the hormone binding. Soluble receptors for other cytokines (interleukin-1, -2, -4, and -6; tumor necrosis factor; etc.) have been identified, and they are also known to act as competitive inhibitors by blocking the binding of cytokines to their respective membrane receptors (48).
Liu et al. (49) recently reported that soluble leptin receptor is capable of binding leptin with a high affinity and that the presence of the soluble leptin receptor can inhibit leptin binding to a membrane receptor. If this is indeed the case, then high soluble leptin receptor levels may be implicated in the development of leptin resistance in diabetes and in pregnancy and may thus play a role in any excessive weight gain seen in these conditions. We do not know at this point whether a rise in soluble leptin receptor levels is associated with any change in the number of the membrane receptors. We know, however, that Ob-Re, i.e. a soluble form of the leptin receptor, is present in several regions of the body, including the hypothalamus (9). This raises the possibility either of a direct interaction at this level or of an indirect action through modification of leptin transport to hypothalamic centers.
Elevated soluble leptin receptor levels in insulin-treated diabetic subjects raise the question of whether insulin could be potentially involved in the regulation of leptin receptor levels. This, in turn, might contribute to increased leptin resistance and weight gain in this group. To our best knowledge to date, however, there are no data on the relationship between insulin and soluble leptin receptor.
In our study we have clearly demonstrated that not only the total, but also free, leptin levels are significantly elevated during human pregnancy. The significance of this physiological phenomenon and the role of placentally derived leptin in energy metabolism and fat deposition during different stages of human pregnancy remain to be explored. Our observation of the difference in the soluble leptin receptor levels between normal and IDDM women suggests a differential regulation of the leptin system via the specific leptin receptor in humans. In view of the published work on competitive binding between the soluble and membrane leptin receptors, we postulate that differences in soluble leptin receptor levels in disease states may provide a mechanism of resistance to the action of leptin in regulating appetite, metabolic rate, and body weight.
Received June 18, 1998.
Revised October 7, 1998.
Accepted October 12, 1998.
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